4-amino-isonipecotic acid



United States Patent 3,330,836 4-AMI1I0-ISONIPECOTIC ACID Rudolf G. Griot, F lorham Park, N.J., assiguor to Sandoz Ind, Hanover, NJ. No Drawing. Fiied Mar. 24, 1964, Ser. No. 354,431 5 Claims. (Cl. 260294.3)

This invention provides compounds which are interesting not only because they form a novel type of a-amino acid, but also because they are useful as starting materials in the preparation of a new class of heterocyclic compounds, which are useful as tranquilizers and blood pressure reducing agents. The new class of heterocyclic compounds -is not the subject matter of this invention.

The compounds of this invention are 4-amino-4-carboXy-piperidines (4-arnino-isonipecotic acids) OOOH wherein R is either a hydrogen atom (H) or lower alkyl, e.g. methyl, ethyl, propyl, isopropyl and butyl, but preferably methyl,

which are prepared by hydrolyzing the Orresponding hydantoins. To prepare compound (I) wherein R is a hydrogen atom, i.e. 4 amino-4-carboxy-piperidine (4-aminoisonipecotic acid), it is necessary to stabilize the stalting material in the preparation of the corresponding-hydam tOin to prevent polymerization. A carbobenzoxy grouping (Cbz) is employed for this purpose, and the reaction scheme follows course (A) Alternatively, 'a benzyl group (Bz) protects the 4-piperi done against polymerization and either of the courses (B) is employed.

Hl l 0 0 HzN C-OH KCN (NH-Q2003 2 4 (e) EtOH/HzO 60% k \N t t I ([311 (f) Bz Bz Hg/PtOa Hz/PtOz in AcOH in AcOH 3,330,836 Patented July 11, 1967 Said new class of heterocyclic compounds is prepared according to the following reaction schemes:

N NCH ll/ 0 wherein R has the aforesaid meaning, e.g. methyl.

Reaction (C) is conducted under reflux in methanol. The reaction with 1 carbobenzoxy-S-ethoxy-1,4-diazacycloheptaneA produces about a 45 percent (by weight) yield in twenty-four hours.

Reaction (D) is conducted in concentrated acetic acid. Adrnixture of (II) with an acetic acid solution of hydrobromic acid results in the production of (111) as a precipitate (in the form of its trihyd-robromide) For reaction (E) the trihydrobromide is converted to its free base according to known procedures, and the free base (dissolved in formic acid) is then admixed with formaldehyde over a boiling water-bath to produce (IV). Compounds (III) and (IV) are members of the noted new class of compounds which have the above-indicated utilities.

In the examples which follow, the parts and percentages are by Weight unless otherwise specified, and the temperatures are in degrees centrigrade. The relationship between parts by weight and parts by volume is the same as that between the kilogram and the liter.

EXAMPLE 1 4-amino-4-carboxy-1-methyl-piperidine C O OH Reflux 22 parts of 8 methyl 1,3,8 triazaspiro [4,5]- EXAMPLE 4 decane-2,4-dione [Mailey, Everett A., and Day, Allan R., J. Organic Chemistry, 22, 1061 1957) in 125 parts PPmdme by volume of 60 percent sulfuric acid for twenty-four (c) HBr/AOOH hours (oilbath 160; reaction mixture at about 130). Cool the resulting clear solution to 20, and thereafter dilute same with 250 parts by volume of water. Pass the thus-diluted solution slowly through a column (twice the volume of the water of dilution) of DOWEX50WX8.

Rinse the ion exchanger sequentially with 100 parts by volume of water and with 1000 parts by volume of methanol. Thereafter elute the amino acid from the ion exchanger with 6000 parts by volume of a 5 percent solu-- tion of ammonia (NH in methanol.

Evaporate the eluate to dryness. There are thus obtained 13 parts of crystalline title compound, melting point (M.P.) 286 (decomp.)

EXAMPLE 2 8-carb0benz0xy-1 ,3,8-triazaspir0 [4,5 decane-2,4-dione 0:? EN (I? HN 0:0

KCN

(N114) 2C a 'lS thus obtained. Isolate (c) by passing the saponification product through DOWEX-SOW-X-S.

Compound (g) is prepared from (f), and compound (d) is prepared from (it) according to this procedure.

Dissolve (c) in a minimum amount of acetic acid (AcOH). Admix with the resulting solution an excess of hydrogen bromide (in 4 N AcOH) at room temperature for four hours. The dihydrobromide of the title compound (d) is thus obtained. The free base is prepared conven- 10 tionally therefrom.

Compound (11) is prepared from (f), and compound (d) is prepared from (g) according to the procedure of this example.

15 The carbobenzoxy group of compound (0) is alternatively removed by hydrogenolytic cleavage with platinum oxide (PtO catalyst in AcOH.

It is thought that the invention and its advantages will be understood from the foregoing description. It is apparent that various changes may be made in the intermediates as well as in the final products without departing from the spirit and scope of the invention or sacrificing its material advantages.

What is claimed is: 1. A compound of the formula )3 H (3H3 Hg) CH3 30 HL'N/ \?=O 'wherein D R is a member selected from the group consisting of a hydrogen atom and lower alkyl. 2. 1-methyl-4-amino-4-carboxy-piperidine. 3. 4-amino-4-carboxy-piperidine. 40 4.1-carbobenZoxy-4-amino4-carboxy-piperidine. 5. 1-benzyl-4-amiuo-4-carboxy-piperidine.

References Cited UNITEDSTATES PATENTS 3,041,344 6/1962 Janssen 260294.3 X 3,125,574 3/1964 Janssen 260-294 3,238,216 3/1966 Janssen 260-294 WALTER A. MODANCE, Primary Examiner.

NICHOLAS S. RIZZO, Examiner.

JOSE TOVAR, Assistant Examiner. 

1. A COMPOUND OF THE FORMULA 